Various diphosphonate materials, including dichloromethane diphosphonic acid and ethane-1-hydroxy-1,1-diphosphonic acid and their salts and esters, are known to be effective in inhibiting deposition and mobilization of calcium phosphate in the body. As a result, these compounds are useful in the treatment and prevention of pathological calcification and hard tissue demineralization conditions. See, U.S. Pat. No. 3,683,080, Francis, issued Aug. 8, 1972. Radio-tagged diphosphonates, especially ethane-1-hydroxy-1,1-diphosphonic acid and dichloromethane diphosphonic acid, have been taught to be effective in the treatment of calcific tumors. U.S. Pat. No. 3,965,254, Francis, issued June 22, 1976. When used in this way, the diphosphonate group locates the molecule at the site of the calcific tumor, while the treatment is provided by the radioisotope portion. There has also been a suggestion that (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate, a substance which can cause significant undesirable side effects, may act to inhibit tumor-induced osteolysis when administered to breast cancer patients having hypercalcemia. S. J. M. Von Bruekelen, et al., Inhibition of Osteolytic Bone Lesions by APD, Lancet, Volume 1, pages 803-805 (Apr. 14, 1979). However, there has been no suggestion in the art that any of these organophosphonates is useful in minimizing tumor cell metastasis to bone, i.e., that these compounds represent a therapeutic alternative for use early in the development of the cancer to minimize the spread of cancer cells from a primary tumor site to the skeleton.
Orr, et al., concluded, in a study utilizing rat mammary tumor cells, that a factor(s) which is chemotactic for tumor cells is produced by bone and is released when the bone is resorbed. These data led to the hypothesis that the release of this chemotactic factor(s) causes tumor cells which have migrated from the main tumor site to become attracted and attached to bone, beginning the formation of a new metastasized tumor. See William Orr, et al., Chemotatic Responses of Tumor Cells to Products of Absorbing Bone, Science, 203, 176-179 (1979).
It has now been found that the use of ethane-1-hydroxy-1,1-diphosphonic acid, dichloromethane diphosphonic acid or their pharmaceutically-acceptable salts and esters, compounds which are known to be safely administered to humans and animals, significantly reduces the incidence of tumor cell metastasis to bone.
It is, therefore, an object of the present invention to provide a safe and effective method for inhibiting the formation of tumor cell metastases without teating the underlying cancer itself in humans and animals having metastatic cancer involving the skeleton.